Formulation and aerosol canisters, inhalers, and the like containing the formulation

ABSTRACT

Formulations containing pharmaceutical active agent, propellant, and water at least partially adsorbed on or absorbed within one or more nylon pellets or nylon components of, for example, an inhaler such as a metered dose inhaler. Canisters, typically sealed canisters, containing such formulations. Inhalers, such as metered dose inhalers, containing such canisters. Methods of making and using the same.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 62/507,313, filed May 17, 2017, the disclosure of whichis incorporated by reference in its entirety herein.

TECHNICAL FIELD

The present disclosure relates to formulations used for, as an example,an inhaled dosage form, as well as to aerosol canisters, inhalers,metered dose inhalers, and the like containing the same.

BACKGROUND

Inhaler formulations comprising pharmaceutical active agents are knownin the art. Known compositions may not be acceptable for use with alldrugs. For example, some drugs may not be stable in known compositions.

SUMMARY

A composition can comprise a liquid comprising a propellant, thepropellant comprising one or more of HFA-134a and HFA-227, one or morepharmaceutical active agents dissolved or dispersed in the liquid; andone or more nylon pellets, and water. At least some of the water isadsorbed on or absorbed within the one or more nylon pellets.

A method of maintaining a water level in a pressurized aerosol canistercan comprise soaking one or more nylon pellets in water to form one ormore water soaked pellets, optionally removing water from the surface ofthe one or more water soaked pellets, forming an aerosol composition byadding the one or more pellets to a composition comprising apharmaceutical active agent and a liquid comprising one or more ofHFA-134a and HFA-227. The aerosol composition can be added to a canisterthe canister pressurized to form a pressurized canister.

DETAILED DESCRIPTION

Throughout this disclosure, singular forms such as “a,” “an,” and “the”are often used for convenience; however, it should be understood thatthe singular forms are meant to include the plural unless the singularalone is explicitly specified or is clearly indicated by the context.

Some terms used in this application have special meanings, as definedherein. All other terms will be known to the skilled artisan, and are tobe afforded the meaning that a person of skill in the art at the time ofthe invention would have given them.

Elements in this specification that are referred to as “common,”“commonly used,” and the like, should be understood to be common withinthe context of the compositions, articles, such as inhalers and metereddose inhalers, and methods of this disclosure; this terminology is notused to mean that these features are present, much less common, in theprior art. Unless otherwise specified, only the Background section ofthis Application refers to the prior art.

The “particle size” of a single particle is the size of the smallesthypothetical hollow sphere that could encapsulate the particle.

The “mass median diameter” of a plurality of particles refers to thevalue for a particle diameter at which 50% of the mass of particles inthe plurality of particles have a particle size smaller than the valueand 50% of the mass of particles in the plurality of particle have aparticle size greater than the value.

The “ex-actuator size” of a plurality of particles refers to the massmedian aerodynamic diameter (sometimes abbreviated as “MMAD”) of theplurality of particles after the plurality of particles has passedthrough the actuator of an inhaler, such as a metered dose inhaler, asmeasured by the procedure described in the United States Pharmacopeia<601>.

“Weight percent” or “percent by weight,” when describing the amount ofcomponent in a composition refers to percent weight of the componentbased on the weight of the entire composition. Weight percent issometimes abbreviated “wt. %.”

“Fine particle dose” is determined according to 2015 United StatesPharmacopia test <601>.

“Fine Particle Mass,” often abbreviated “FPM,” is in this disclosuredetermined mathematically using Copley Inhaler Testing Data AnalysisSoftware (CITDAS) (Copley Scientific LTD., Nottingham, United Kingdom).

“Fine Particle Fraction,” often abbreviated “FPF,” is determinedaccording to 2015 United States Pharmacopia test <601> and is calculatedas [FPM/(sum of sample content for throat assembly, cups 1-7, MOC, andthe filter)]×100.

The “canister size” of a plurality of particles is used here to refer tothe mass mean diameter of the plurality of particles in a canister atthe time that the formulation is prepared. Canister size can bedetermined, for example, using light scattering methods.

The term “nylon pellets” refers to a mass of nylon; this term is usedfor convenience, but is not intended to convey any particular size orshape of nylon. Nylon pellets can be of any size or shape of nylon.

When the concentration of ipratropium is discussed in this disclosure,for convenience it is referred to in terms of the concentration ofipratropium bromide monohydrate, unless the disclosure specificallyrefers to another form, such as another salt, hydrate, or anhydrousform. It should therefore be understood that if another form or salt ofipratropium is used, the concentration of that other form or salt shouldbe calculated on a basis relative to ipratropium bromide monohydrate. Aperson of ordinary skill in the relevant arts can easily perform thiscalculation by comparing the molecular weight of the form or salt ofipratropium that is used to the molecular weight of ipratropium bromidemonohydrate.

Aerosol formulations containing pharmaceutical active agents must beformulated properly in order to provide stability to the pharmaceuticalactive agent or agents and prevent overly rapid degradation of thepharmaceutical active agent or agents. This is important because overlyrapid degradation of the pharmaceutical active agent or agents leads tounacceptable shelf-life of inhalers containing the aerosol formulations.

The stability of pharmaceutical active agents can, in many cases, beenhanced by minimizing the amount of water in the aerosol formulation,for example, by excluding water from the manufacturing process and thensealing the inhaler in a water-resistant pouch, such as a foil pouch,often with a desiccant inside the pouch, to prevent uptake of water fromthe environment.

This application relates to a newly-recognized problem with thatapproach. Specifically, some pharmaceutically active agents are notsuitably stable when the water level is too low. For example, somepharmaceutical active agents are in the form of hydrates. When the waterlevel is too low, the hydrate can partially or totally dehydrate. Thepartially or totally dehydrated pharmaceutical active agent can eitherbe pharmaceutically unacceptable or can further degrade.

Thus, this application recognizes a formerly unknown problem,specifically, that the level of water in many aerosol compositions ofpharmaceutical active agents must be maintained within particularlimits, including a lower limit, in order to maintain stability of somepharmaceutical active agents. This is in contrast to what was formerlyunderstood, namely, that the water content should be kept as low aspossible. In response to this problem, the present Application providesaerosol formulations designed to contain water, for example, apre-determined amount of water, and maintain the water in desirableconcentrations. Pressurized canisters containing such solutions,inhalers containing such pressurized canisters, and methods of makingsuch formulations, canisters, and inhalers, are also provided. Theaerosol formulations contain a liquid comprising one or more of HFA 134aand HFA-227, a pharmaceutically active agent dissolved or dispersed inthe liquid, one or more nylon pellets, and water. At least some of thewater is adsorbed on or absorbed in the one or more nylon pellets. Thewater content can be controlled based on the treatment of the nylonpellets, as described in detail herein.

The nylon pellets can be made from any type of nylon. Nylon nomenclatureis well known to those of skill in the art. Nylons are often named withthe word “nylon” followed by two numbers, which may be separated by acomma, or by the letters “PA” followed by one or two numbers, whereintwo numbers are often separated by a slash. Letters can also be used inthe naming scheme, and this nomenclature will be familiar to the artisanor ordinary skill. Typical nylons that may be used include one of nylon6,6, PA6, PA11, PA12, PA6/66, PA6/6T, PA4T, PA66, PA410, PA6I/6T,PA66/6T, PA12/MACMI, or mixtures thereof. Most commonly, the nyloncomprises nylon 6,6. In many cases, the nylon is nylon 6,6.

When the composition is to be filled into a canister, then the nylonpellet is selected so as to fit inside the canister and not be excludedby the opening through which the canister is filled. The nylon pelletscan therefore be cylinders, round, pill-shaped, capsule-shaped, flat, orany other convenient shape. In some cases, the nylon pellets arecylinders. Because nylon 6,6 can be obtained as a 5 mm diameter rod, itcan be convenient to cut nylon pellets from such a rod, in which casethe nylon pellets can have a diameter of 5 mm and any convenient height.Convenient heights can be, for example, from 1 mm to 20 mm.

HFA 134a and HFA-227 are common propellants used in aerosolformulations. When they are used as a mixture, any suitable mixture ofthe two can be used. For example, the amount of HFA-134a, on a weightpercent basis based on the combined weight of HFA-134a and HFA-227, canbe at least 10%, at least 20%, at least 30%, at least 40%, at least 50%,at least 60%, at least 70%, or at least 80%. In some cases, thepropellant will be primarily HFA-134a. In such cases, the HFA-134acontent of the propellant on a weight percent basis, based on thecombined weight of HFA-134a and HFA-227, can be at least 90%, such as atleast 91%, at least 92%, at least 93%, at least 94%, at least 95%, atleast 96%, at least 97% at least 98%, at least 99%, at least 99.25%, atleast 99.5%, or at least 99.75%. In some cases, the propellant isHFA-134a. The amount of HFA-227, on a weight percent basis based on thecombined weight of HFA-134a and HFA-227, can be at least 10%, at least20%, at least 30%, at least 40%, at least 50%, at least 60%, at least70%, or at least 80%. In some cases, the propellant will be primarilyHFA-227. In such cases, the HFA-227 content of the propellant on aweight percent basis, based on the combined weight of HFA-134a andHFA-227, can be at least 90%, such as at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97% atleast 98%, at least 99%, at least 99.25%, at least 99.5%, or at least99.75%. In some cases the propellant is HFA-227.

The formulation can be a solution. Solution formulations, especially foruse in aerosols, can have several advantages over suspensionformulations. Such advantages include being homogenous so that users donot need to agitate the formulation to ensure a correct dose. Also,because they are homogeneous, solution formulations provide essentiallyidentical amounts of drug per mass of dose for each dose in an inhaler,whereas inhomogeneous suspensions may lack this consistency.

Solution formulations are not required. Suspension formulations are alsopossible. In suspension formulations, the pharmaceutical active agent,and in some cases one or more excipients, are wholly or partiallydispersed in the liquid rather than being dissolved. Such suspensionformulations may, in some cases, have to be agitated or shaken beforeadministrations.

The at least one pharmaceutical active agent can comprise ipratropium.Ipratropium is a cationic material, and is therefore typically used inthe form of one or more physiologically acceptable salts or solvates.Ipratropium bromide is the most common salt. The ipratropium bromide ismost commonly in the form of a hydrate. Typically, the hydrate is amonohydrate. Thus, ipratropium is usually in the form of ipratropiumbromide monohydrate.

The canister size of the particles of ipratropium, such as ipratropiumbromide or ipratropium bromide monohydrate, can be any suitable canistersize. Exemplary suitable canister sizes can be no less than 1micrometer, no less than 1.5 micrometers, no less than 2 micrometers, noless than 2.5 micrometers, no less than 3 micrometers, no less than 3.5micrometers, no less than 4 micrometers, or no less than 4.5micrometers. Exemplary suitable canister sizes can also be no greaterthan 5 micrometers, no greater than 4.5 micrometers, no greater than 4.0micrometers, no greater than 3.5 micrometers, no greater than 3.0micrometers, no greater than 2.5 micrometers, no greater than 2.0micrometers, or no greater than 1.5 micrometers. 1 micrometer to 5micrometers is common.

Ipratropium, such as ipratropium bromide monohydrate, can be present inthe composition in solution or as a dispersed particulate. When used inparticulate form, the ex-actuator size of the ipratropium particles,such as ipratropium bromide or ipratropium bromide monohydrate, can beany suitable ex-actuator size. Exemplary suitable ex-actuator sizes canbe no less than 1 micrometer, no less than 1.5 micrometers, no less than2 micrometers, no less than 2.5 micrometers, no less than 3 micrometers,no less than 3.5 micrometers, no less than 4 micrometers, or no lessthan 4.5 micrometers. Exemplary suitable ex-actuator sizes can also beno greater than 5 micrometers, no greater than 4.5 micrometers, nogreater than 4.0 micrometers, no greater than 3.5 micrometers, nogreater than 3.0 micrometers, no greater than 2.5 micrometers, nogreater than 2.0 micrometers, or no greater than 1.5 micrometers. 1micrometer to 5 micrometers is common.

The ipratropium can be used in any suitable concentration. On a mg/mLbasis, typical concentrations are no less than 0.15, no less than 0.2,no less than 0.3, no less than 0.4, no less than 0.5, no less than 0.6,no less than 0.7, no less than 0.8, no less than 0.9, no less than 1.0,no less than 1.1, no less than 1.2, no less than 1.3, no less than 1.4,no less than 1.5, no less than 1.6, no less than 1.7, no less than 1.8,no less than 1.9, or no less than 2.0. Typical concentrations are alsono greater than 2.0, no greater than 1.9, no greater than 1.8, nogreater than 1.7, no greater than 1.6, no greater than 1.5, no greaterthan 1.4, no greater than 1.3, no greater than 1.2, no greater than 1.1,no greater than 1.0, no greater than 0.9, no greater than 0.8, nogreater than 0.7, no greater than 0.6, or no greater than 0.5. Commonconcentrations are from 0.2 mg/mL to 1.72 mg/mL. For some applications,a concentration of 0.68 to 0.86 mg/mL is used. For other applications, aconcentration of 0.33 to 0.42 mg/mL is used.

Any suitable concentration of ipratropium can be used. When theconcentration of ipratropium is expressed in terms of mg/mL ofipratropium bromide monohydrate, then the concentration of ipratropiumcan be no more than 0.15 mg/ml, no more than 0.14 mg/ml, no more than0.13 mg/ml, no more than 0.12 mg/ml, no more than 0.11 mg/ml, no morethan 0.10 mg/ml, no more than 0.09 mg/ml, no more than 0.08 mg/ml, nomore than 0.07 mg/ml, no more than 0.06 mg/ml, or no more than 0.05mg/ml. The concentration of ipratropium, again expressed in terms ofipratropium bromide monohydrate, can be no less than 0.05 mg/ml, no lessthan 0.06 mg/ml, no less than 0.07 mg/ml, no less than 0.08 mg/ml, noless than 0.09, no less than 0.1 mg/ml, no less than 0.11 mg/ml, no lessthan 0.12 mg/ml, or no less than 0.13 mg/ml. Particular embodiments useipratropium in an amount of about 0.08 mg/ml to about 0.12 mg/ml, suchas 0.08 mg/ml to 0.12 mg/ml, about 0.09 mg/ml to about 0.11 mg/ml, suchas 0.09 mg/ml to 0.11 mg/ml, about 0.1 mg/ml, or in some cases 0.1mg/ml. When expressed in terms of wt %, the concentration of ipratropium(in terms of ipratropium bromide monohydrate) is often no greater than0.015, no greater than 0.014, no greater than 0.0125, or no greater than0.012. When expressed in terms of wt %, the concentration of ipratropium(in terms of ipratropium bromide monohydrate) is often no less than0.005, no less than 0.006, no less than 0.0075, no less than 0.008, orno less than 0.01.

The ipratropium can be present in any suitable concentration in theformulation. The concentration is often expressed in terms ofipratropium bromide monohydrate; if a different ipratropium salt orhydrate is used, a person of ordinary skill in the art is able tocalculate the concentration of the particular ipratropium salt used interms of ipratropium bromide monohydrate using the ratio of the molarmass of the ipratropium salt being used to the molar mass of ipratropiumbromide monohydrate.

Albuterol, sometimes known as salbutamol, can also be used as thepharmaceutical active agent. The albuterol can be a free base, but ismore typically in the form of one or more physiologically acceptablesalts or solvates. Albuterol sulfate is most common.

The albuterol, such as albuterol sulfate, is most commonly inparticulate form. The canister size of the particles of albuterol, suchas albuterol sulfate, can be any suitable canister size. Exemplarysuitable canister sizes can be no less than 1 micrometer, no less than1.0 micrometers, no less than 1.5 micrometers, no less than 2micrometers, no less than 2.5 micrometers, no less than 3 micrometers,no less than 3.5 micrometers, no less than 4 micrometers, or no lessthan 4.5 micrometers. Exemplary suitable canister sizes can also be nogreater than 5 micrometers, no greater than 4.5 micrometers, no greaterthan 4.0 micrometers, no greater than 3.5 micrometers, no greater than3.0 micrometers, no greater than 2.5 micrometers, no greater than 2.0micrometers, or no greater than 1.5 micrometers. 1 micrometer to 5micrometers is common.

The ex-actuator size of the albuterol particles, such as albuterolsulfate particles, can be any suitable ex-actuator size. Exemplarysuitable ex-actuator sizes can be no less than 1 micrometer, no lessthan 1.5 micrometers, no less than 2 micrometers, no less than 2.5micrometers, no less than 3 micrometers, no less than 3.5 micrometers,no less than 4 micrometers, or no less than 4.5 micrometers. Exemplarysuitable ex-actuator sizes can also be no greater than 5 micrometers, nogreater than 4.5 micrometers, no greater than 4.0 micrometers, nogreater than 3.5 micrometers, no greater than 3.0 micrometers, nogreater than 2.5 micrometers, no greater than 2.0 micrometers, or nogreater than 1.5 micrometers. 1 micrometer to 5 micrometers is common.

The albuterol, such as albuterol sulfate, can be present in any suitableconcentration in the formulation. When the concentration of albuterol isexpressed in terms of mg/mL, then the concentration of albuterol, basedon albuterol sulfate, can be no less than 1.0, no less than 1.5, no lessthan 1.6, no less than 1.7, no less than 1.8, no less than 1.9, no lessthan 2.0, no less than 2.1, no less than 2.2, no less than 2.3, no lessthan 2.4, no less than 2.5, no less than 2.6, no less than 2.7, no lessthan 2.8, no less than 2.9, no less than 3.0, no less than 3.1, no lessthan 3.2, no less than 3.3, no less than 3.4, no less than 3.5, no lessthan 3.6, no less than 3.7, no less than 3.8, no less than 3.9, no lessthan 4.0, no less than 4.1, no less than 4.2, no less than 4.3, no lessthan 4.4, no less than 4.5, no less than 4.6, no less than 4.8, no lessthan 4.9, no less than 5.0, no less than 5.1, no less than 5.1, no lessthan 5.2, no less than 5.3, no less than 5.4, no less than 5.5, no lessthan 5.6, no less than 5.7, no less than 5.8, no less than 5.9, no lessthan 6.0, no less than 6.1, no less than 6.2, no less than 6.3, no lessthan 6.4, no less than 6.5, no less than 6.6, no less than 6.7, no lessthan 6.8, no less than 6.9, no less than 7.0, no less than 7.1, no lessthan 7.2, no less than 7.3, no less than 7.4, no less than 7.5, no lessthan 7.6, no less than 7.7, no less than 7.8, no less than 7.9, no lessthan 8.0, no less than 8.1, no less than 8.2, no less than 8.3, no lessthan 8.4, no less than 8.5, no less than 8.6, no less than 8.7, no lessthan 8.8, no less than 8.9, no less than 9.0, no less than 9.1, no lessthan 9.2, no less than 9.3, no less than 9.4, no less than 9.5, no lessthan 9.6, no less than 9.7, no less than 9.8, no less than 9.9, no lessthan 10.0, no less than 10.1, no less than 10.2, no less than 10.3, noless than 10.4, no less than 10.5, no less than 10.6, no less than 10.7,no less than 10.8, no less than 10.9, or no less than 11. Also on amg/mL basis, the concentration of albuterol can be no greater than 11,no greater than 10.9, no greater than 10.8, no greater than 10.7, nogreater than 10.6, no greater than 10.5, no greater than 10.4, nogreater than 10.3, no greater than 10.2, no greater than 10.1, nogreater than 10.0, no greater than 9.9, no greater than 9.8, no greaterthan 9.7, no greater than 9.6, no greater than 9.5, no greater than 9.4,no greater than 9.3, no greater than 9.2, no greater than 9.1, nogreater than 9.0, no greater than 8.9, no greater than 8.8, no greaterthan 8.7, no greater than 8.6, no greater than 8.5, no greater than 8.4,no greater than 8.3, no greater than 8.2, no greater than 8.1, nogreater than 8.0, no greater than 7.9, no greater than 7.8, no greaterthan 7.7, no greater than 7.6, no greater than 7.5, no greater than 7.4,no greater than 7.3, no greater than 7.2, no greater than 7.1, nogreater than 7.0, no greater than 6.9, no greater than 6.8, no greaterthan 6.7, no greater than 6.6, no greater than 6.5, no greater than 6.4,no greater than 6.3, no greater than 6.2, no greater than 6.1, nogreater than 6.0, no greater than 5.9, no greater than 5.8, no greaterthan 5.7, no greater than 5.6, no greater than 5.5, no greater than 5.4,no greater than 5.3, no greater than 5.2, no greater than 5.1, nogreater than 5.0, no greater than 4.9, no greater than 4.8, no greaterthan 4.7, no greater than 4.6, no greater than 4.5, no greater than 4.4,no greater than 4.3, no greater than 4.2, or no greater than 4.1. Commonconcentrations are from 1.2 mg/mL to 9.8 mg/mL. For some applications, aconcentration of 3.9 to 4.9 mg/mL is employed. For other applications, aconcentration of 1.9 to 2.4 mg/mL is employed.

Other pharmaceutical active agents can also be used. The albuterol andipratropium can be used in combination.

One or more surfactants can also be used. Surfactants are particularlyuseful to facilitate dispersion of pharmaceutical active agent particlesor dissolution of pharmaceutical active agent particles in theformulation. However, surfactant-free formulations can be advantageousfor some purposes, and surfactant is not required unless otherwisespecified.

When surfactant is included, any pharmaceutically acceptable surfactantcan be used. Most such surfactants are suitable for use with an inhaler.Typical surfactants include oleic acid, sorbitan monooleate, sorbitantrioleate, soya lecithin, polyethylene glycol, polyvinylpyrrolidone, orcombinations thereof. Oleic acid, polyvinylpyrrolidone, or a combinationthereof is most common. A combination of polyvinylpyrrolidone andpolyethylene glycol is also commonly employed. When polyvinylpyrrolidoneis employed, it can have any suitable molecular weight. Examples ofsuitable weight average molecular weights are from 10 to 100kilodaltons, typically from 10 to 50, 10 to 40, 10 to 30 or 10 to 20kilodaltons. When polyethylene glycol is employed, it can be anysuitable grade. PEG 1000 and PEG 300 are most commonly employed.

When used, the surfactant is typically present, on a weight percentbasis, in an amount no less than 0.0001, no less than 0.01, no less than0.02, no less than 0.03, no less than 0.04, no less than 0.05, no lessthan 0.06, no less than 0.07, no less than 0.08, no less than 0.09, noless than 0.10, no less than 0.11, no less than 0.12, no less than 0.13,no less than 0.14, no less than 0.15, no less than 0.16, no less than0.17, no less than 0.18, no less than 0.19, no less than 0.2, no lessthan 0.21, no less than 0.22, no less than 0.23, no less than 0.24, noless than 0.25, no less than 0.26, no less than 0.27, no less than 0.28,no less than 0.29, no less than 0.3, no less than 0.4, no less than 0.5,no less than 0.6, no less than 0.7, no less than 0.8, no less than 0.9,or no less than 1. The surfactant is also typically present, on a weightpercent basis, in an amount no greater than 1, no greater than 0.9, nogreater than 0.8, no greater than 0.7, no greater than 0.6, no greaterthan 0.5, no greater than 0.4, no greater than 0.3, no greater than0.29, no greater than 0.28, no greater than 0.27, no greater than 0.26,no greater than 0.25, no greater than 0.24, no greater than 0.23, nogreater than 0.22, no greater than 0.21, no greater than 0.20, nogreater than 0.19, no greater than 0.18, no greater than 0.17, nogreater than 0.16, no greater than 0.15, no greater than 0.14, nogreater than 0.13, no greater than 0.12, no greater than 0.11, nogreater than 0.10, no greater than 0.09, no greater than 0.08, nogreater than 0.07, no greater than 0.06, no greater than 0.05, nogreater than 0.04, no greater than 0.03, no greater than 0.02, or nogreater than 0.01. Concentration ranges can be from 0.0001 wt. % to 1wt. %, such as 0.001 wt. % to 0.1 wt. %. Particular applications use0.01 wt. % surfactant.

Particularly, oleic acid can be used in any of the abovementionedconcentrations. Particularly, polyvinylpyrrolidone can be used in any ofthe abovementioned concentrations. Particularly, a combination ofpolyethylene glycol and polyvinylpyrrolidone can be used in any of theabovementioned concentrations. Particularly, sorbitan trioleate can beused in any of the abovementioned concentrations.

Ethanol can be used to ensure adequate concentration of drug can bedissolved or suspended in the liquid. On a weight percent basis, theamount of ethanol used, if any, is typically up to 20, up to 19, up to18, up to 17 up to 16, no greater than 15.5, no greater than 15, nogreater than 14.5, no greater than 13, no greater than 12, no greaterthan 11, or no greater than 10. The amount of ethanol used can also be,on a weight percent basis, no less than 10, no less than 11, no lessthan 12, no less than 13, no less than 14, no less than 14.5, no lessthan 15, no less than 15.5, no less than 16, no less than 17 or no lessthan 18. In many cases, the ethanol is about 13 to about 17 percent byweight, 13 to 17 percent by weight, such as about 14 to about 16 percentby weight, 14 to 16 percent by weight, about 14.5 to about 15.5 percentby weight, 14.5 to 15.5 percent by weight, or, in one particular case,about 15 percent by weight or more particularly 15 percent by weight.Ethanol is not always required to obtain a sufficiently highconcentration of drug in solution or suspension, and some drugs cannotbe formulated with ethanol for stability or other reasons. Ethanol-freeformulations can also be employed.

One or more ex-actuator size affecting compounds may be included.Ex-actuator size affecting compounds can change the size of the drugparticles as measured after actuation of an inhaler, such as a metereddose inhaler, containing the composition. Surfactants can be used forthis purpose. Most pharmaceutically acceptable surfactants are suitablefor use with an inhaler. Typical surfactants include oleic acid,sorbitan monooleate, sorbitan trioleate, soya lecithin, polyethyleneglycol, polyvinylpyrrolidone, or combinations thereof. Oleic acid,polyvinylpyrrolidone, or a combination thereof is most common. Acombination of polyvinylpyrrolidone and polyethylene glycol is alsocommonly employed. When polyvinylpyrrolidone is employed, it can haveany suitable molecular weight. Examples of suitable weight averagemolecular weights are from 10 to 100 kilodaltons, typically from 10 to50, 10 to 40, 10 to 30 or 10 to 20 kilodaltons. When polyethylene glycolis employed, it can be any suitable grade. PEG 100 and PEG 300 are mostcommonly employed. Most commonly, however, the ex-actuator sizeaffecting compound is glycerol.

When used, the ex-actuator size affecting compound, particularlyglycerol, can be present in a weight percent basis of no more than 2.0%,no more than 1.9%, no more than 1.8%, no more than 1.7%, no more than1.6%, no more than 1.55%, no more than 1.5%, no more than 1.45%, no morethan 1.4%, no more than 1.3%, no more than 1.2%, no more than 1.1%, nomore than 1.0%, no more than 0.9%, no more than 0.8%, or no more than0.75%. The ex-actuator size affecting compound, particularly glycerol,can be present in a weight percent basis of no less than 1.0%, no lessthan 1.1%, no less than 1.2%, no less than 1.3%, no less than 1.4%, noless than 1.45%, no less than 1.5%, no less than 1.55%, no less than1.6%, no less than 1.7%, no less than 1.8%, or no less than 1.9%. Thus,the ex-actuator size affecting compound, particularly glycerol, can bepresent, on a weight percent basis, in about 0.7% to about 1.7%, 0.7% to1.7%, about 0.8% to 1.6%, 0.8% to 1.6%, about 0.9 to about 1.6, 0.9 to1.6%, about 1.0% to about 1.5%, or 1.0% to 1.5%. Particular examples useeither 1.0% or 1.5%.

One or more stabilizing agents can be included. The one or morestabilizing agents can be any agents that increase the stability of theformulation. The stabilizing agents can be, for example, antioxidantssuch as sacrificial antioxidants. Any pharmaceutically acceptablestabilizing agent can be used. One particular stabilizing agent iscitric acid or a salt thereof.

When employed, citric acid or the salt thereof can be present, on aweight percent basis, in amounts of no less than 0.075%, no less than0.08%, no less than 0.09%, no less than 0.10%, no less than 0.11%, noless than 0.12%, no less than 0.13%, no less than 0.14%, no less than0.15%, no less than 0.16%, no less than 0.17%, no less than 0.18%, noless than 0.19%, or no less than 0.20%. The citric acid can be present,on a weight percent basis, in amounts of no more than 0.20%, 0.19%,0.18%, 0.17%, 0.16%, 0.15%, 0.14%, 0.13%, 0.12%, 0.11%, 0.1%, or 0.09%.Exemplary amounts of citric acid, on a weight percent basis, are about0.12% to about 0.18%, 0.12% to 0.18%, about 0.13% to about 0.17%, 0.13%to 0.17%, about 0.14% to about 0.16%, 0.14% to 0.16%, about 0.15%, or0.15%. When a salt of citric acid is used, the weight percent values inthis paragraph should be understood to be based on the weight of freecitric acid (i.e., without considering the weight of the cation). Mostcommonly, citric acid alone is used.

The compositions can be formed by admixing all of the components. Theone or more nylon pellets are typically soaked with water before beingadded to the composition. Thus, when added to the composition, the nylonpellets have water adsorbed to their surface or absorbed in the pellets,for example, within pores in the pellets or in the spaces betweenpolymer chains such that the water can swell the one or more nylonpellets. In some cases, the surface water can be removed from the one ormore nylon pellets, for example by blotting, before addition to thecomposition.

The amount of water in the pellets can be controlled, for example, byvarying the soaking time and the pellet geometry. After soaking andoptional surface drying, the amount of water in the pellets can bequantified, for example by gravimetric analysis, before addition to thecomposition. The total amount of water in the pellets will depend on thedesired concentration of water in the composition. The pellets need notbe completely saturated with water, and in most cases will not becompletely saturated with water.

Once added to the composition, the nylon pellets can release water overtime, thereby providing a target concentration of water in theformulation. When the composition is present in a sealed system,particularly an aerosol canister, the use of soaked nylon pellets asdescribed herein can maintain the target level of water in thecomposition for a prolonged period of time.

Many inhalers are equipped with nylon components, such as valve stems,O-rings, gaskets, or the like. Such components can also be pre-soaked inwater and optionally dried of surface water before being affixed to thecanister, in which case they can also serve to help maintain the waterlevel in the composition.

In some cases, the pellets can be omitted entirely. In such cases, oneor more nylon components of the inhaler, such as the valve stem, anO-ring, a gasket, or the like, are soaked in water to provide thedesired water levels. This works the same way as the use of nylonpellets, except that the appropriate amount of water is added by way ofadsorption on or absorption into one or more nylon components of theinhaler. All of the remainder of the description herein applies to theuse of water-soaked nylon components in the same way as it applies tothe use of nylon pellets.

The target concentration range of water in the liquid will depend on thespecific pharmaceutical active agent or agents being used. In mostcases, the concentration of the water dissolved or dispersed in theliquid is between 50 ppm and 500 ppm based on the liquid and anycomponents dissolved or dispersed in the liquid. This concentration canbe achieved by using an appropriate amount of water in the nylonpellets. The appropriate amount of water will depend on the compositionof the liquid, including both the propellant choice and the presence orabsence of hydrophilic components, such as ethanol and glycerol, andsurfactants, such as those discussed above. The actual concentration ofwater in the liquid can be determined by known means, such as by KarlFischer analysis. Thus, the person of skill in the art can readilydetermine how much water should be adsorbed on or absorbed in thepellets by determining the actual water content of the liquid, forexample by using Karl Fischer analysis. After determining the actualwater content of the liquid, the artisan can increase or decrease thewater concentration in the liquid by changing the number, size, orsoaking time of the pellets and then re-checking the actual watercontent of the liquid as an iterative process until the desired waterlevel is reached.

When the pellets are cylindrical in shape, then for pellets of the samediameter the amount of water taken up by the pellets in a given time canincrease approximately linearly with the pellet length and beapproximately proportional to the pellet surface area. The proportionalrelationship between water uptake and surface area can hold for othershapes as well. This proportionality may not apply as the pelletsapproach or reach their saturation limit where they cannot hold anyadditional water. The skilled artisan using the guidance provided hereinwill be able to reach the desired water levels within the liquid afterroutine optimization of the information provided in this disclosure.

The use of soaked nylon as described herein overcomes a practicalproblem in adding a suitable amount of water to an aerosol composition.As discussed above, the amount of water required is often very low.Depending on the particular pharmaceutical active agent, the tolerancefor error can also be very low. For instance, achieving a water contentof 250 ppm in a canister that holds a total volume of 10 g means addingonly 2.0 mg of water to the canister, which in the art of fillingaerosol canisters is considered to be a very small volume that isdifficult to add consistently in a repeated manner, such as in amanufacturing setting. This problem is exacerbated when the canister isfilled by a cold-filling technique, wherein filling takes place at lowtemperatures, such as around −60° C., because ambient water readilycondenses on or in the canister at such temperatures. In order toprevent such ambient water condensation, the atmosphere at the time offilling is often very dry, for example at a dew point of −80° C. In suchdry conditions, it is difficult to accurately add a particular amountwater to the canister because some of the water can readily evaporate.

The use of soaked nylon as described herein can ameliorate all of thesepractical problems by removing the need to add water directly tocanisters. Once the desired shape, number, and size of pellets, as wellas their soaking time, is determined (such as according to the guidanceprovided herein), then the pellets can be easily counted out andrepeatably added to canisters in a manufacturing setting.

Inhaler

Any of the above-described formulations can be used with any type ofinhaler. Metered dose inhalers, sometimes referred to as MDIs, are mostcommon. When the inhaler is a metered dose inhaler, any metered doseinhaler can be employed. Suitable metered dose inhalers are known in theart.

For example, the above-described formulations can be present in acanister, such as a sealed canister. Such sealed canister can containany of the above-described formulations under pressure, particularlyunder a pressure greater than ambient atmospheric pressure.

Typical metered dose inhalers for the pharmaceutical formulationsdescribed herein contain an aerosol canister fitted with a valve. Thecanister can have any suitable volume. The canister brimful capacitywill depend on the volume of the formulation that is to be used to fillthe canister. In typical applications, the canister will have a volumefrom 5 mL to 500 mL, such as, for example 10 mL to 500 mL, 25 mL to 400mL, 5 mL to 50 mL, 8 mL to 30 mL, 10 mL to 25 mL, or 50 to 250 mL. Thecanister will typically have sufficient volume to contain enoughmedicament for delivering an appropriate number of doses. Theappropriate number of doses is discussed herein. The valve is typicallyaffixed, or crimped, onto the canister by way of a cap or ferrule. Thecap or ferrule is often made of aluminum or an aluminum alloy, which istypically part of the valve assembly. One or more seals can be locatedbetween the canister and the ferrule. The seals can be one or more ofO-ring seals, gasket seals, and the like. The valve is typically ametered dose valve. Typical valve sizes range from 20 microliters to 100microliters. Specific valve size that are commonly employed include 25,50, 60, and 63 microliter valve sizes.

The container and valve are typically used with an actuator. Mostactuators have a patient port, which is typically a mouthpiece, fordelivering the formulation contained in the canister. The patient portcan be configured in a variety of ways depending on the intendeddestination of the formulation. For example, a patient port designed foradministration to the nasal cavities will generally have an upward slopeto direct the formulation to the nose. The actuator is most commonlymade out of a plastic material. Typical plastic materials for thispurpose include at least one of polyethylene and polypropylene. TypicalMDIs have an actuator with a nozzle. In use, the aerosol spray canemerge from this nozzle before exiting the mouthpiece of the actuator.The nozzle can be characterized by an orifice diameter and a jet length.Any suitable orifice diameter can be used. Typical orifice diameters arefrom 0.2 mm to 0.65 mm, with 0.2 mm to 0.4 mm being particularly usefulfor delivery of solution formulations, such as the solution formulationsdiscussed herein. Typical orifice jet length is from 0.5 mm to 1 mm.Specific examples include orifice diameters of 0.3 mm, 0.3 mm, or 0.4mm, any of which can have a jet length of 0.8 mm.

A metered dose valve is typically present, and is often located at leastpartially within the canister and at least partially in communicationwith the actuator. Typical metered dose valves include a meteringchamber that is at least partially defined by an inner valve bodythrough which a valve stem passes. The valve stem can be biasedoutwardly by a compression spring to be in a sliding sealing engagementwith an inner tank seal and outer diaphragm seal. The valve can alsoinclude a second valve body in the form of a bottle emptier. The innervalve body, which is sometimes referred to as the primary valve body,defines, in part, the metering chamber. The second valve body, which issometimes referred to as the secondary valve body, defines, in part, apre-metering region (sometimes called a pre-metering chamber) inaddition to serving as a bottle emptier. The outer walls of the portionof the metered dose valve that are located within the canister, as wellas the inner walls of the canister, defined a formulation chamber forcontaining the pharmaceutical formulation.

In use, the pharmaceutical formulation can pass from the formulationchamber into the metering chamber. In moving to the metering chamber,the formulation can pass into the above-mentioned pre-metering chamberthrough an annular space between the secondary valve body (or a flangeof the secondary valve body) and the primary valve body. Pressing thevalve stem towards the interior of the container actuates the valve,which allows the pharmaceutical formulation to pass from the meteringchamber through a side hole in the valve stem, through an outlet in thevalve stem, to an actuator nozzle, and finally through the patient portto the patient. When the valve stem is released, more of thepharmaceutical formulation enters the valve, typically into thepre-metering chamber, through an annular space and then into themetering chamber.

The pharmaceutical formulation can be placed into the canister by anyknown method. The two most common methods are cold filling and pressurefilling. In a cold filling process, the pharmaceutical formulation ischilled to an appropriate temperature, which is typically −50° C. to−60° C. for formulations that use propellant HFA 134a, propellant HFA227, or a combination thereof, and added to the canister. The metereddose valve is subsequently crimped onto the canister. When the canisterwarms to ambient temperature, the vapor pressure associated with thepharmaceutical formulation increases thereby providing an appropriatepressure within the canister.

In a pressure filling method, the metered dose valve can be firstcrimped onto the empty canister. Subsequently, the formulation can beadded through the valve into the container by way of applied pressure.Alternatively, the non-volatile components can be first added to theempty canister before crimping the valve onto the canister. Thepropellant can then be added through the valve into the canister by wayof applied pressure.

The total dose of ipratropium, such as ipratropium bromide or moreparticularly ipratropium bromide monohydrate, that is delivered in asingle actuation can be any suitable dose depending on the nature of thecondition and patient population that the inhaler is designed to treat.Typically, the total dose delivered, in micrograms, is no less than 3,such as no less than 3.25, no less than 3.75, no less than 4, or no lessthan 4.25. Typically, the total dose delivered, in micrograms, is nomore than 6.5, no more than 6.25, no more than 6.0, no more than 5.75,no more than 5.5, no more than 5.25, no more than 5, or no more than4.75. Most commonly, the dose is from 4 micrograms to 5.5 micrograms peractuation.

Typical inhalers, such as metered dose inhalers, are designed to delivera specified number of doses of the pharmaceutical formulation. A dose issometimes deliverable by a single actuation of the inhaler, but can bedeliverable by two, three, four, or more actuations. In most cases, thespecified number of doses is from 10 to 120, such as from 30-120. Onecommonly employed metered dose inhaler is designed to provide 60 doseswhereby each dose is delivered in two actuations; this can be employedwith any of the formulations or inhaler types described herein.

The inhaler, particularly when it is a metered dose inhaler, can containa dose counter for counting the number of doses. Suitable dose countersare known in the art, and are described in, for example, U.S. Pat. Nos.8,740,014, 8,479,732, and U.S. Patent Application Publication No.2012/0234317, and U.S. Pat. No. 8,814,035, all of which are incorporatedby reference for their disclosures of dose counters.

One exemplary dose counter, which is described in detail in U.S. Pat.No. 8,740,014 (which is hereby incorporated by reference for itsdisclosure of the dose counter) has a fixed ratchet element and atrigger element that is constructed and arranged to undergo reciprocalmovement coordinated with the reciprocal movement between an actuationelement in an inhaler and the dose counter. The reciprocal movementtypically comprises an outward stroke (outward being with respect to theinhaler) and a return stroke. The return stroke returns the triggerelement to the position that it was in prior to the outward stroke. Acounter element is also included in this type of dose counter. Thecounter element is constructed and arranged to undergo a predeterminedcounting movement each time a dose is dispensed. The counter element isbiased towards the fixed ratchet and trigger elements and is capable ofcounting motion in a direction that is substantially orthogonal to thedirection of the reciprocal movement of the trigger element.

The counter element in the above-described dose counter comprises afirst region for interacting with the trigger member. The first regioncomprises at least one inclined surface that is engaged by the triggermember during the outward stroke of the trigger member. This engagementduring the outward stroke causes the counter element to undergo acounting motion. The counter element also comprises a second region forinteracting with the ratchet member. The second region comprises atleast one inclined surface that is engaged by the ratchet element duringthe return stroke of the trigger element causing the counter element toundergo a further counting motion, thereby completing a countingmovement. The counter element is normally in the form of a counter ring,and is advanced partially on the outward stroke of the trigger element,and partially on the return stroke of the trigger element. As theoutward stroke of the trigger typically corresponds to the depression ofa valve stem that causes firing of the valve (and, in the case of ametered dose inhaler, also meters the contents) and the return stroketypically corresponds to the return of the valve stem to its restingposition, this dose counter allows for precise counting of doses.

Another suitable dose counter, which is described in detail in U.S. Pat.No. 8,479,732 (which is incorporated by reference for its disclosure ofdose counters) is specially adapted for use with a metered dose inhaler.This dose counter includes a first count indicator having a firstindicia bearing surface. The first count indicator is rotatable about afirst axis. The dose counter also includes a second count indicatorhaving a second indicia bearing surface. The second count indicator isrotatable about a second axis. The first and second axes are disposedsuch that they form an obtuse angle. The obtuse angle mentioned abovecan be any obtuse angle, but is advantageously 125 to 145 degrees. Theobtuse angle permits the first and second indicia bearing surface toalign at a common viewing area to collectively present at least aportion of a medication dosage count. One or both of the first andsecond indicia bearing surfaces can be marked with digits, such thatwhen viewed together through the viewing area the numbers provide a dosecount. For example, one of the first and second indicia bearing surfacemay have “hundreds” and “tens” place digits, and the other may have“ones” place digits, such that when read together the two indiciabearing surfaces provide a number between 000 and 999 that representsthe dose count.

Yet another suitable dose counter is described in U.S. PatentApplication Publication No. 2012/0234317 (hereby incorporated byreference for its disclosure of dose counters). Such a dose counterincludes a counter element that undergoes a predetermined countingmotion each time a dose is dispensed. The counting motion is typicallyvertical or essentially vertical. A count indicating element is alsoincluded. The count indicating element, which undergoes a predeterminedcount indicating motion each time a dose is dispensed, includes a firstregion that interacts with the counter element.

The counter element has regions for interacting with the countindicating element. Specifically, the counter element comprises a firstregion that interacts with a count indicating element. The first regionincludes at least one surface that it engaged with at least one surfaceof the first region of the aforementioned count indicating element. Thefirst region of the counter element and the first surface of the countinducing element are disposed such that the count indicating membercompletes a count indicating motion in coordination with the countingmotion of the counter element, during and induced by the movement of thecounter element, the count inducing element undergoes a rotational oressentially rotational movement. In practice, the first region of thecounter element or the counter indicating element can comprise, forexample, one or more channels. A first region of the other element cancomprise one or more protrusions adapted to engage with said one or morechannels.

Yet another dose counter is described in U.S. Pat. No. 8,814,035 (herebyincorporated by reference for its disclosure of dose counters). Such adose counter is specially adapted for use with an inhaler with areciprocal actuator operating along a first axis. The dose counterincludes an indicator element that is rotatable about a second axis. Theindicator element is adapted to undergo one or more predeterminedcount-indicating motions when one or more doses are dispensed. Thesecond axis is at an obtuse angle with respect to the first axis. Thedose counter also contains a worm rotatable about a worm axis. The wormis adapted to drive the indicator element. It may do this, for example,by containing a region that interacts with and enmeshes with a region ofthe indicator element. The worm axis and the second axis do notintersect and are not aligned in a perpendicular manner. The worm axisis also, in most cases, not disposed in coaxial alignment with the firstaxis. However, the first and second axes may intersect.

At least one of the various internal components of an inhaler, such as ametered dose inhaler, as described herein, such as one or more of thecanister, valve, gaskets, seals, O-rings, and the like, can be coatedwith one or more coatings. Some of these coatings provide a low surfaceenergy. Such coatings are not required because they are not necessaryfor the successful operation of all inhalers.

Some coatings that can be used are described in U.S. Pat. Nos.8,414,956, 8,815,325 and U.S. Patent Application No. 2012/0097159, allof which are incorporated by reference for their disclosure of coatingsfor inhalers and inhaler components.

A first acceptable coating can be provided by the following method:

-   -   a) providing one or more component of the inhaler, such as the        metered dose inhaler,    -   b) providing a primer composition comprising a silane having two        or more reactive silane groups separated by an organic linker        group,    -   c) providing a coating composition comprising an at least        partially fluorinated compound,    -   d) applying the primer composition to at least a portion of the        surface of the component,    -   e) applying the coating composition to the portion of the        surface of the component after application of the primer        composition.

The at least partially fluorinated compound will usually comprise one ormore reactive functional groups, with the one or each one reactivefunctional group usually being a reactive silane group, for example ahydrolysable silane group or a hydroxysilane group. Such reactive silanegroups allow reaction of the partially fluorinated compound with one ormore of the reactive silane groups of the primer. Often such reactionwill be a condensation reaction.

One exemplary silane that can be used has the formula

X_(3-m)(R¹)_(m)Si-Q-Si(R²)_(k)X_(3-k)

wherein R¹ and R² are independently selected univalent groups, X is ahydrolysable or hydroxy group, m and k are independently 0, 1, or 2 andQ is a divalent organic linking group.

Useful examples of such silanes include one or a mixture of two or moreof 1,2-bis(trialkoxysilyl) ethane, 1,6-bis(trialkoxysilyl) hexane,1,8-bis(trialkoxysilyl) octane, 1,4-bis(trialkoxysilylethyl)benzene,bis(trialkoxysilyl)itaconate, and4,4′-bis(trialkoxysilyl)-1,1′-diphenyl, wherein any trialkoxy group maybe independently trimethoxy or triethoxy.

The coating solvent usually comprises an alcohol or a hydrofluoroether.

If the coating solvent is an alcohol, preferred alcohols are C₁ to C₄alcohols, in particular, an alcohol selected from ethanol, n-propanol,or iso-propanol or a mixture of two or more of these alcohols.

If the coating solvent is a hydrofluoroether, it is preferred if thecoating solvent comprises a C₄ to C₁₀ hydrofluoroether. Generally, thehydrofluoroether will be of formula

C_(g)F_(2g+1)OC_(h)H_(2h+1)

wherein g is 2, 3, 4, 5, or 6 and his 1, 2, 3 or 4. Examples of suitablehydrofluoroethers include those selected from the group consisting ofmethyl heptafluoropropylether, ethyl heptafluoropropylether, methylnonafluorobutylether, ethyl nonafluorobutylether and mixtures thereof.

The polyfluoropolyether silane is typically of the formula

R^(f)Q¹ _(v)[Q² _(w)-[C(R⁴)₂—Si(X)_(3-x)(R⁵)_(x)]_(y)]_(z)

wherein:

R^(f) is a polyfluoropolyether moiety;

Q¹ is a trivalent linking group;

each Q² is an independently selected organic divalent or trivalentlinking group;

each R⁴ is independently hydrogen or a C₁₋₄ alkyl group;

each X is independently a hydrolysable or hydroxyl group;

R⁵ is a C₁₋₈ alkyl or phenyl group;

v and w are independently 0 or 1, x is 0 or 1 or 2; y is 1 or 2; and zis 2, 3, or 4.

The polyfluoropolyether moiety R^(f) can comprise perfluorinatedrepeating units selected from the group consisting of —(C_(n)F_(2n)O)—,—(CF(Z)O)—, —(CF(Z)C_(n)F₂O)—, —(C_(n)F_(2n)CF(Z)O)—, —(CF₂CF(Z)O)—, andcombinations thereof; wherein n is an integer from 1 to 6 and Z is aperfluoroalkyl group, an oxygen-containing perfluoroalkyl group, aperfluoroalkoxy group, or an oxygen-substituted perfluoroalkoxy group,each of which can be linear, branched, or cyclic, and have 1 to 5 carbonatoms and up to 4 oxygen atoms when oxygen-containing oroxygen-substituted and wherein for repeating units including Z thenumber of carbon atoms in sequence is at most 6. In particular, n can bean integer from 1 to 4, more particularly from 1 to 3. For repeatingunits including Z the number of carbon atoms in sequence may be at mostfour, more particularly at most 3. Usually, n is 1 or 2 and Z is a —CF₃group, more particularly wherein z is 2, and R^(f) is selected from thegroup consisting of —CF₂O(CF₂O)_(m)(C₂F₄O)_(p)CF₂—,—CF(CF₃)O(CF(CF₃)CF₂O)_(p)CF(CF₃)—, —CF₂O(C₂F₄O)_(p) CF₂—,—(CF₂)₃O(C₄F₈O)_(p)(CF₂)₃—,—CF(CF₃)—(OCF₂CF(CF₃))_(p)O—C_(t)F_(2t)—O(CF(CF₃)CF₂O)_(p)CF(CF₃)—,wherein t is 2, 3 or 4 and wherein m is 1 to 50, and p is 3 to 40.

A cross-linking agent can be included. Typical cross-linking agentsinclude tetramethoxysilane; tetraethoxysilane; tetrapropoxysilane;tetrabutoxysilane; methyl triethoxysilane; dimethyldiethoxysilane;octadecyltriethoxysilane; 3-glycidoxy-propyltrimethoxysilane;3-glycidoxy-propyltriethoxysilane; 3-aminopropyl-trimethoxysilane;3-aminopropyl-triethoxysilane; bis (3-trimethoxysilylpropyl) amine;3-aminopropyl tri(methoxyethoxyethoxy) silane; N(2-aminoethyl)3-aminopropyltrimethoxysilane; bis(3-trimethoxysilylpropyl) ethylenediamine;3-mercaptopropyltrimethoxysilane; 3-mercaptopropyltriethoxysilane;3-trimethoxysilyl-propylmethacrylate; 3-triethoxysilypropylmethacrylate;bis (trimethoxysilyl) itaconate; allyltriethoxysilane;allyltrimethoxysilane; 3-(N-allylamino)propyltrimethoxysilane;vinyltrimethoxysilane; vinyltriethoxysilane; and mixtures thereof.

The component to be coated can be pre-treated before coating, typicallyby cleaning. Cleaning can be by way of a solvent, typically ahydrofluoroether, e.g. HFE72DE, or an azeotropic mixture of about 70%w/w trans-dichloroethylene; 30% w/w of a mixture of methyl and ethylnonafluorobutyl and nonafluoroisobutyl ethers.

The above-described first acceptable coating is particularly useful forcoating valve components, including one or more of valve stems, bottleemptiers, springs, and tanks, as well as canisters, such as metered doseinhalers, as described herein. This coating system can be used with anytype of inhaler and any formulation described herein.

A second type of coating that can be used comprises apolyphenylsulphone. The polyphenylsulphone typically has the followingchemical structure

In this structure, n is the number of repeat units, which is typicallysufficient to provide a weight average molecular weight from 10,000 to80,000 daltons, for example, from 10,000 to 30,000 daltons.

Other polymers, such as polyethersulphones, fluoropolymers such as PTFE,FEP, or PFA, can also be included. However, such other polymers areoptional, and it is often advantageous to exclude them.

Polyphenylsulphones can be difficult to apply by a solvent castingprocess. Thus, a special solvent system that is viable for use in amanufacturing setting can be employed for coating polyphenylsulphones.One such solvent system employs a (1) first solvent that has aHildebrand Solubility Parameter of at least 20.5 MPa^(0.5) and at most25 MPa^(0.5), such as from 21 MPa^(0.5) to 23.5 MPa^(0.5); and (2) atleast 20% by volume, often greater than 70% or greater than 80% byvolume, of at least one 5-membered aliphatic, cyclic, or heterocyclicketone based on the total volume of the solvent system. Optionally, athird component, namely a linear aliphatic ketone, can be included inamounts less than 5% by volume of the total volume of the solventsystem.

Any first solvent that has a Hildebrand Solubility Parameter of at least20.5 MPa^(0.5) and at most 25 MPa^(0.5) can be used, so long as theother components of the solvent system are as stated above. Some suchfirst solvents are also 5-membered aliphatic, cyclic, or heterocyclicketones, in which case the first solvent and the 5-membered aliphatic,cyclic, or heterocyclic ketone can be the same material. Other suchsolvents include acetonitrile.

The 5-membered aliphatic, cyclic, or heterocyclic ketone is typically agamma lactone, such as gamma-butyrolactone, or a gamma lactam, such as apyrolidone like 2-pyrrolidone, or an alkyl substituted 2-pyrrolidonelike N-alkyl-2-pyrrolidones such as N-methyl-2-pyrrolidine (sometimesknown by the acronym NMP). Other examples of 5-membered aliphatic,cyclic, or heterocyclic ketone that can be used include 2-methylcyclopentanone, 2-ethyl cyclopentanone, and2-[1-(5-methyl-2-furyl)butyl]cyclopentanone. Cyclopentanone is the mostcommonly used material.

The optional linear aliphatic ketone can be any linear aliphatic ketone,and is typically acetone, although methyl ethyl ketone is alsofrequently employed.

The above-described second acceptable coating can be used on any type ofinhaler, but is particularly useful for components of metered doseinhalers.

A third acceptable coating can be used to lower the surface energy ofany component of an inhaler, such as a metered dose inhaler, but isparticularly useful for valve stems, particularly those made of acetalpolymer, as well as for stainless steel or aluminum components,particularly those used in canisters.

Such a coating can be formed on a component of an inhaler by thefollowing process:

-   -   a) forming a non-metal coating on at least a portion of a        surface of the medicinal inhalation device or a component of a        medicinal inhalation device, respectively, said coating having        at least one functional group;    -   b) applying to at least a portion of a surface of the non-metal        coating a composition comprising an at least partially        fluorinated compound comprising at least one functional group;        and    -   c) allowing at least one functional group of the at least        partially fluorinated compound to react with at least one        functional group of the non-metal coating to form a covalent        bond.

The at least one functional group of the non-metal coating is typicallya hydroxyl group or silanol group. In most cases, the non-metal coatinghas a plurality of functional groups, particularly silanol groups, andcan be formed, for example by plasma coating an organosilicone withsilanol groups on the inhaler or one or more inhaler components. Typicalorganosilicon compounds include trimethylsilane, triethylsilane,trimethoxysilane, triethoxysilane, tetramethylsilane, tetraethylsilane,tetramethoxysilane, tetraethoxysilane, hexamethylcyclotrisiloxane,tetramethylcyclotetrasiloxane, tetraethylcyclotetrasiloxane,octamethylcyclotetrasiloxane, hexamethyldisiloxane,bistrimethylsilylmethane, and mixtures thereof. Most commonly, one ormore of trimethylsilane, triethylsilane, tetramethylsilane,tetraethylsilane, bistrimethylsilylmethane are employed, withtetramethylsilane being most common. In addition to the organosilicon,the plasma can contain one or more of oxygen, a silicon hydride,particularly silicon tetrahydride, disilane, or a mixture thereof, orboth. After deposition, the non-metal coating can be a diamond-likeglass or carbon-like glass containing, on a hydrogen free basis, 20atomic percent or more of carbon and 30 atomic percent of more ofsilicon and oxygen combined.

The non-metal coating is often exposed to an oxygen plasma or coronatreatment before applying the partially fluorinated compound. Mosttypically, an oxygen plasma treatment under ion bombardment conditionsis employed.

The at least partially fluorinated compound often contains one or morehydrolysable groups, such as oxyalkly silanes, typically ethyoxy ormethoxy silanes. A polyfluoropolyether segment, which in particularcases is a perfluorinated polyfluoroether, is typically used.Poly(perfluoroethylene) glycol is most common. Thus, the at leastpartially fluorinated compound can include a polyfluropolyether linkedto one or more functional silanes by way of, for example, acarbon-silicon, nitrogen-silicon, or sulfer-silicon bond.

Examples of at least partially fluorinated compounds that can be usedinclude those having the following formula:

R_(f)[Q-[C(R)₂—Si(Y)_(3-x)(R^(1a))_(x)]_(y)]_(z)

wherein:

-   -   R_(f) is a monovalent or multivalent polyfluoropolyether        segment;    -   Q is an organic divalent or trivalent linking group;    -   each R is independently hydrogen or a C₁₋₄ alkyl group;    -   each Y is independently a hydrolysable group;    -   R^(1a) is a C₁₋₈ alkyl or phenyl group;    -   x is 0 or 1 or 2;    -   y is 1 or 2; and    -   z is 1, 2, 3, or 4.

Typically, R_(f) comprises perfluorinated repeating units selected fromthe group consisting of —(C_(n)F_(2n)O)—, —(CF(Z)O)—,—(CF(Z)C_(n)F_(2n)O)—, —(C_(n)F_(2n)CF(Z)O)—, —(CF₂CF(Z)O)—, andcombinations thereof; wherein n is an integer from 1 to 6 and Z is aperfluoroalkyl group, an oxygen-containing perfluoroalkyl group, aperfluoroalkoxy group, or an oxygen-substituted perfluoroalkoxy group,each of which can be linear, branched, or cyclic and have 1 to 5 carbonatoms and up to 4 oxygen atoms when oxygen-containing oroxygen-substituted and wherein for repeating units including Z thenumber of carbon atoms in sequence is at most 6. Particular examples ofthis compound are those where z is 1, R^(f) is selected from the groupconsisting of C₃F₇O(CF(CF₃)CF₂O)_(p)CF(CF₃)—, CF₃O(C₂F₄O)_(p)CF₂—,C₃F₇O(CF(CF₃)CF₂O)_(p)CF₂CF₂—, C₃F₇O(CF₂CF₂CF₂O)_(p)CF₂CF₂—,C₃F₇O(CF₂CF₂CF₂O)_(p)CF(CF₃)— and CF₃O(CF₂CF(CF₃)O)_(p)(CF₂O)X—, whereinX is CF₂—, C₂F₄—, C₃F₆—, or C₄F₈— and wherein the average value of p is3 to 50. Other particular examples include those wherein z is 2, R_(f)is selected from the group consisting of —CF₂O(CF₂O)_(m)(C₂F₄O)_(p)CF₂—,—CF(CF₃)O(CF(CF₃)CF₂O)_(p)CF(CF₃)—, —CF₂O(C₂F₄O)_(p)CF₂—,—(CF₂)₃O(C₄F₈O)_(p)(CF₂)₃—,—CF(CF₃)—(OCF₂CF(CF₃))_(p)O—C_(t)F_(2t)—O(CF(CF₃)CF₂O)_(p)CF(CF₃)—,wherein t is 2, 3 or 4 and wherein m is 1 to 50, and p is 3 to 40. Mostcommonly R_(f) is one of —CF₂O(CF₂O)_(m)(C₂F₄O)_(p)CF₂—,—CF₂O(C₂F₄O)_(p)CF₂—, and—CF(CF₃)—(OCF₂CF(CF₃))_(p)O—(C_(t)F_(2t))—O(CF(CF₃)CF₂O)_(p)CF(CF₃)—, tis 2, 3, or 4, and the average value of m+p or p+p or p is from about 4to about 24. Q is commonly selected from the group consisting of—C(O)N(R)—(CH₂)_(k)—, —S(O)₂N(R)—(CH₂)_(k)—, —(CH₂)_(k)—,—CH₂O—(CH₂)_(k)—, —C(O)S—(CH₂)_(k)—, —CH₂OC(O)N(R)—(CH₂)_(k)—, and

when R is hydrogen or C₁₋₄ alkyl, and k is 2 to about 25. In othercommon cases, Q is selected from the group consisting of—C(O)N(R)(CH₂)₂—, —OC(O)N(R)(CH₂)₂—, —CH₂O(CH₂)₂—, or—CH₂—OC(O)N(R)—(CH₂)₂—, R is hydrogen or C₁₋₄ alkyl, and y is 1.

Upon applying appropriate at least partially fluorinated compounds tothe non-metallic coating, at least one covalent bond can form betweenthe two, thereby completing the coating.

Yet another suitable coating is fluorinated ethylene propylenecopolymer, sometimes known as FEP. FEP coatings are particularly usefulfor coating one or more internal surfaces of a canister, and can be usedin association with other coatings that can be applied to either otherinternal surfaces of a canister or to other components of the inhaler.

Packaging

The inhaler containing the canister and formulation can be stored bysealing within a moisture-barrier pouch. The moisture-barrier pouch canhave one or more layers, and typically has at least one moisture barrierlayer. The moisture barrier layer can be any layer that inhibits orprevents moisture from moving through the pouch. The moisture barrierlayer is typically aluminum foil, but other moisture barrier layers,such as polymeric moisture barrier layers, can also be employed. It isalso possible to store the inhaler in other ways, so the moisturebarrier pouch is not used in all cases.

Contrary to the teachings of the prior art, the moisture barrier pouch,when used, typically does not include a desiccant within the pouch. Thisis because, contrary to the suggestions in the prior art that the waterlevel should be minimized, the inventors have recognized that too low ofa water level can induce degradation of some drugs. A desiccant thatremoves water from the formulation can, therefore, actually have adestabilizing effect on the drug in cases where the drug is sensitive todry conditions. Instead, the nylon pellets as described herein can beused to maintain the water level and prevent overdrying of theformulation.

LIST OF EXEMPLARY EMBODIMENTS

The following embodiments are meant to be illustrative, and are notintended to be limiting unless otherwise specified.

1. A composition comprising

a liquid comprising a propellant, the propellant comprising one or moreof HFA-134a and HFA-227

one or more pharmaceutical active agents dissolved or dispersed in theliquid; and

one or more nylon pellets; and

water, wherein

at least some of the water is adsorbed on or absorbed within the one ormore nylon pellets.

1a. A composition comprising

a liquid comprising a propellant, the propellant comprising one or moreof HFA-134a and HFA-227

one or more pharmaceutical active agents dissolved or dispersed in theliquid;

one or more nylon components; and

water, wherein

at least some of the water is adsorbed on or absorbed within the one ormore nylon components.

2. The composition of embodiment 1, wherein at least one of the one ormore pharmaceutical active agents is a hydrate.

3. The composition of any of the preceding embodiments, wherein at leastone of the one or more pharmaceutical active agents is a hydrate ofipratropium or a hydrate of an ipratropium salt.

4. The composition of any of the preceding embodiments, wherein at leastone of the one or more pharmaceutical active agents is ipratropium or asalt or hydrate thereof.

5. The composition of any of the preceding embodiments, wherein at leastone of the one or more pharmaceutical active agents is ipratropiumbromide.

6. The composition of any of the preceding embodiments, wherein at leastone of the one or more pharmaceutical active agents is ipratropiumbromide monohydrate.

7. The composition of any of the preceding embodiments, wherein theconcentration of ipratropium, expressed in terms of ipratropium bromidemonohydrate, is no more than 0.15 mg/ml, no more than 0.14 mg/ml, nomore than 0.13 mg/ml, no more than 0.12 mg/ml, no more than 0.11 mg/ml,no more than 0.10 mg/ml, no more than 0.09 mg/ml, no more than 0.08mg/ml, no more than 0.07 mg/ml, no more than 0.06 mg/ml, or no more than0.05 mg/ml.

8. The composition of any of the preceding embodiments, wherein theconcentration of ipratropium, expressed in terms of ipratropium bromidemonohydrate, is no less than 0.05 mg/ml, no less than 0.06 mg/ml, noless than 0.07 mg/ml, no less than 0.08 mg/ml, no less than 0.09, noless than 0.1 mg/ml, no less than 1.1 mg/ml, no less than 1.2 mg/ml, orno less than 1.3 mg/ml.

9. The composition of any of the preceding embodiments, wherein theconcentration of ipratropium, expressed in terms of ipratropium bromidemonohydrate, is about 0.08 mg/ml to about 0012 mg/ml, 0.08 mg/ml to 0.12mg/ml, about 0.09 mg/ml to about 0.11 mg/ml, or 0.09 mg/ml to 0.11mg/ml.

9a. The composition of any of the preceding embodiments, wherein theconcentration of ipratropium, expressed in terms of ipratropium bromidemonohydrate, is about 0.1 mg/ml or 0.1 mg/ml.

9b. The composition of any preceding embodiment, wherein theconcentration of ipratropium expressed as wt % of ipratropium bromidemonohydrate is no less than 0.005, no less than 0.006, no less than0.0075, no less than 0.008, or no less than 0.01.

9c. The composition of any of the preceding embodiments wherein the theconcentration of ipratropium expressed as wt % of ipratropium bromidemonohydrate is no greater than 0.015, no greater than 0.014, no greaterthan 0.0125, or no greater than 0.012.

10. The composition of any of the preceding embodiments wherein theweight percent of ethanol is no greater than 20, no greater than 19, nogreater than 18, no greater than 17, no greater than 16, no greater than15.5, no greater than 15, no greater than 14.5, no greater than 13, nogreater than 12, no greater than 11, or no greater than 10.

11. The composition of any of the preceding embodiments, wherein theweight percent of ethanol is no less than 10, no less than 11, no lessthan 12, no less than 13, no less than 14, no less than 14.5, no lessthan 15, no less than 15.5, no less than 16, no less than 17 or no lessthan 18.

12. The composition of any of the preceding embodiments wherein theweight percent of ethanol is from about 13 to about 17, 13 to 17, about14 to about 16, 14 to 16, about 14.5 to about 15.5, or 14.5 to 15.5.

13. The composition of any of the preceding embodiments, wherein theweight percent of ethanol is about 15 or more particularly 15.

14. The composition of any of the preceding embodiments, wherein theweight percent of citric acid or salt thereof based on the weight ofcitric acid, is less than 0.075%, no less than 0.08%, no less than0.09%, no less than 0.10%, no less than 0.11%, no less than 0.12%, noless than 0.13%, no less than 0.14%, no less than 0.15%, no less than0.16%, no less than 0.17%, no less than 0.18%, no less than 0.19%, or noless than 0.20%.

15. The composition of any of the preceding embodiments, wherein theweight percent of citric acid, or salt thereof based on the weight ofcitric acid, is no more than 0.20%, no more than 0.19%, no more than0.18%, no more than 0.17%, no more than 0.16%, no more than 0.15%, nomore than 0.14%, no more than 0.13%, no more than 0.12%, no more than0.11%, no more than 0.1%, or no more than 0.09%.

16. The composition of any of the preceding embodiments, wherein theweight percent of citric acid, or salt thereof based on the weight ofcitric acid, is 0.12% to about 0.18%, 0.12% to 0.18%, about 0.13% toabout 0.17%, 0.13% to 0.17%, about 0.14% to about 0.16%, 0.14% to 0.16%,about 0.15%, or 0.15%.

17. The composition of any of the preceding embodiments, wherein theweight percent of citric acid or salt thereof, based on the weight ofcitric acid, is, about 0.15%, or 0.15%.

18. The composition of any of the preceding embodiments, wherein thecitric acid or salt thereof is citric acid.

19. The composition of any of the preceding embodiments, whereinglycerol is present, on a weight percent basis, in an amount no morethan 2.0%, no more than 1.9%, no more than 1.8%, no more than 1.7%, nomore than 1.6%, no more than 1.55%, no more than 1.5%, no more than1.45%, no more than 1.4%, no more than 1.3%, no more than 1.2%, no morethan 1.1%, no more than 1.0%, no more than 0.9%, no more than 0.8%, orno more than 0.75%. Thus, the ex-actuator size affecting compound,particularly glycerol, can be present, on a weight percent basis, inabout 0.7% to about 1.7%, 0.7% to 1.7%, about 0.8% to 1.6%, 0.8% to1.6%, about 0.9 to about 1.6, 0.9 to 1.6%, about 1.0% to about 1.5%, or1.0% to 1.5%.

20. The composition of any of the preceding embodiments, whereinglycerol is present, on a weight percent basis, in an amount no lessthan 1.0%, no less than 1.1%, no less than 1.2%, no less than 1.3%, noless than 1.4%, no less than 1.45%, no less than 1.5%, no less than1.55%, no less than 1.6%, no less than 1.7%, no less than 1.8%, or noless than 1.9%.

21. The composition of any of the preceding embodiments wherein theglycerol is present, on a weight percent basis, in about 0.7% to about1.7%, 0.7% to 1.7%, about 0.8% to 1.6%, 0.8% to 1.6%, about 0.9 to about1.6, or 0.9% to 1.6%.

22. The composition of any of the preceding embodiments wherein theglycerol present, on a weight percent basis, in about 1.0% to about1.5%, or 1.0% to 1.5%.

23. The composition of embodiment 22 wherein the glycerol is present, ona weight percent basis, in about 1.0%, more particularly 1%, or whereinthe glycerol is present, on a weight percent basis, in about 1.5%, moreparticularly 1.5%.

24. The composition of any preceding embodiment wherein the compositionloses less than 5 wt % of the ipratropium content after six months ofstorage inside an aerosol canister at a temperature of 25° C. and arelative humidity of 60%.

25. The composition of any of the preceding embodiments, wherein theamount of HFA-134a in the propellant is, on a weight percent basis, atleast 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, or at least 90%, such as at least91%, at least 92%, at least 93%, at least 94%, at least 95%, at least96%, at least 97%, at least 98%, at least 99%, at least 99.25%, at least99.5%, or at least 99.75%, based on the total weight of the propellant.

26. The composition of any of the preceding embodiments, wherein theamount of HFA-227 in the propellant is, on a weight percent basis, atleast 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, or at least 90%, such as at least91%, at least 92%, at least 93%, at least 94%, at least 95%, at least96%, at least 97%, at least 98%, at least 99%, at least 99.25%, at least99.5%, or at least 99.75%, based on the total weight of the propellant.

27. The composition of any of the preceding embodiments, wherein thecomposition further comprises albuterol.

28. The composition of any of the preceding embodiments, wherein thenylon comprises one or more of nylon 6,6, PA6, PA11, PA12, PA6/66,PA6/6T, PA4T, PA66, PA410, PA6I/6T PA66/6T, PA12/MACMI, or mixturesthereof.

29. The composition of any of the preceding embodiments, wherein thenylon comprises nylon 6,6.

30. The composition of any of the preceding embodiments, wherein thenylon is nylon 6,6.

31. The composition of any of the preceding embodiments, wherein atleast some of the water is dissolved or dispersed in the liquid.

32. The composition of embodiment 31 wherein concentration of the waterdissolved or dispersed in the liquid is between 50 ppm and 300 ppm basedon the liquid and any components dissolved or dispersed in the liquid.

33. The composition of any of embodiments 31-32, wherein the nylonpellets having a cylindrical shape.

33a. The composition of any of the preceding embodiments, wherein thetotal surface area of the one or more nylon components or pellets isbetween 4 mm² and 160 mm² per gram of liquid propellant.

33b. The composition of any of the preceding embodiments, wherein thetotal surface area of the one or more nylon components or pellets isbetween 70 mm² and 1600 mm², and the total mass of liquid propellant isbetween 10 grams and 16 grams.

33c. The composition of any of the preceding embodiments, wherein thetotal surface area of the one or more nylon components or pellets isbetween 35 mm² and 1000 mm², and the total mass of liquid propellant isbetween 4 grams and 10 grams.

34. An aerosol canister containing a formulation of any precedingembodiment under a pressure that is greater than ambient atmosphericpressure.

35. The aerosol canister of embodiment 34 comprising at least onesurface having a primer composition comprising a silane having two ormore reactive silane groups separated by an organic linker groupdisposed thereon, wherein the primer composition has a coatingcomposition comprising an at least partially fluorinated compounddisposed thereon.

36. The aerosol canister of embodiment 35, wherein the at leastpartially fluorinated compound is an at least partially fluorinatedpolyethersilane.

37. An aerosol canister of embodiment 34 comprising at least one surfacehaving a coating comprising polyphenylsulphone.

38. An aerosol canister of embodiment 34 comprising at least one surfacehaving a coating comprising a diamond-like glass or carbon-like glass.

39. An inhaler comprising the formulation of any of embodiments 1-33 orthe aerosol canister of any of embodiments 34-38.

40. The inhaler of embodiment 39 that is a metered dose inhaler.

41. The inhaler of any of embodiments 39-40 comprising a valve stem.

42. The inhaler of any of embodiments 39-41 comprising a dose counter.

43. The inhaler of any of embodiments 39-42, comprising at least onenylon component, the at least one nylon component having water absorbedtherein or adsorbed thereon.

44. The inhaler of embodiment 43, wherein the at least one nyloncomponent is selected from a valve stem, an O-ring, and a gasket.

45. A moisture barrier pouch comprising at least one moisture barrierlayer, the moisture barrier pouch having an interior and an exterior,the interior of the moisture barrier pouch comprising an inhaler of anyof embodiments 39-44.

46. The moisture barrier pouch of embodiment 45, wherein the interior ofthe pouch does not contain a desiccant.

47. The moisture barrier pouch of any of embodiments 45 or 46, whereinthe at least one moisture barrier layer comprises aluminum foil.

48. A method of making an inhaler of any of embodiments 39-42 comprisingsealing a canister containing a composition of any of embodiments 1-38.

49. The method of embodiment 48, wherein at least a part of thecomposition of any of embodiments 1-38 is cold-filled into the canister.

50. The method of embodiment 48, wherein at least a part of thecomposition of any of embodiments 1-38 is filled into the canister underpressure.

51. The method of embodiment 48, wherein at least a part of thecomposition of any of embodiments 1-38 is filled into the canister underthe application of pressure greater than atmospheric pressure.

52. A method of maintaining a water level in a pressurized aerosolcanister, the method comprising

soaking one or more nylon pellets in water to form one or more watersoaked pellets,

optionally removing water from the surface of the one or more watersoaked pellets,

forming an aerosol composition of any of embodiments 1-33 by combiningthe one or more pellets with a composition comprising a pharmaceuticalactive agent and a liquid comprising one or more of HFA-134a andHFA-227.

adding the aerosol composition to a canister and pressurizing thecanister to form an aerosol canister of any of embodiments 34-36.

53. The method of embodiment 52, wherein the water level is apre-determined water level.

54. A method of maintaining a water level in a pressurized aerosolcanister, the method comprising

soaking one or more nylon internal components of an inhaler in water toform one or more water soaked nylon components,

optionally removing water from the surface of the one or more watersoaked nylon components

adding the one or more nylon internal components and an aerosolcomposition of any of embodiments 1-33 to the canister.

55. The method of embodiment 54, wherein the water level is apre-determined water level.

56. The method of any of embodiments 52-55 wherein the water level orpre-determined water level is between 50 ppm and 500 ppm based on theliquid and any components dissolved or dispersed in the liquid.

EXAMPLES

HFA-134a (1,1,1,2-tetrafluoroethane) was obtained from the DuPontCorporation (Wilmington, Del.). HFA-227(1,1,1,2,3,3,3-heptafluoropropane) was obtained from the SolvayCorporation (Brussels, Belgium). Ipratropium bromide monohydrate wasobtained from Sifavitor-Infa Group (Milan, Italy). Albuterol sulfate wasobtained from Teva Active Pharmaceutical Ingredients (Petah Tivka,Israel). Deionized water was used.

Rods of nylon 6,6 (5 mm in diameter) were obtained from Direct PlasticsLtd. (Sheffield, UK) and stored under ambient conditions.

Metered dose inhaler canisters were prepared using 15 mL deep drawnaluminum cans and 3M retention valves with EPDM (ethylene-propylenediene terpolymer) elastomer seals both obtained from the 3M Corporation(Clitheroe, UK). For Examples 3 to 5, the internal surface of each canwas coated with FEP (fluorinated ethylene propylene copolymer).

In Tables 1-2 and 4-6, the surface area of each nylon pellet wascalculated using the equation for calculating the surface area of aright circular cylinder (Equation 1) where r=the radius of the circularend (or base) of the pellet and h=the height (or length) of the pellet.When more than one nylon pellet was added to a canister the “TotalSurface Area of Pellet(s)” that is reported is the sum of the surfaceareas for the added pellets.

Surface area of a pellet=(2πrh)+2(πr ²)  Equation 1:

The length of each pellet was measured using a digital caliper (AbsoluteDigimatic, Mitutoyo Corporation, Kawasaki, Japan). When more than onenylon pellet was added to a canister the “Total Length of Pellet(s)”that is reported is the sum of the measured lengths for the addedpellets.

Example 1

Pellets of differing lengths were cut from the nylon 6,6 rods using ascalpel and were then soaked in a water bath at room temperature for 12hours. The pellets were removed from the water bath and their surfaceswere thoroughly wiped dry using paper toweling. One or more pellets werethen added to an aluminum can and the can was then immediatelycold-filled with about 12.5-14 grams of HFA-134a. The metering valve wasthen attached by crimping it to the can to form a finished metered doseinhaler canister. Nine different canisters (canisters 1-9) were preparedaccording to this procedure, each with a different number of pelletsand/or pellet length. Two additional canisters were prepared ascomparative examples (A and B) in which the same procedure was followedexcept that no pellets were added to the canister. The comparativecanisters provided a baseline water content for HFA-134a filledcanisters. The finished canisters were stored in a valve-up orientationat ambient conditions for one month. At the end of the storage period,the water content in the propellant of each canister was determinedusing a Karl Fischer test. A Karl Fischer coulometric titrator(Mitsubishi CA-100 model available from the Mitsubishi ChemicalCorporation, Tokyo, Japan) was used to determine the water content inthe canister. The titration cell contained Anode solution Coulomat AGand Cathode solution Coulomat CG. The instrument was calibrated prior touse with a known amount of a certified 10 mg/ml water standard solution.To determine the amount of water in each canister, an aliquot of theformulation was fired directly from the metering valve into thetitration vessel via a metal cannula (needle). The water in the KarlFischer solution was then titrated and the water concentration wascalculated.

In Table 1, for each canister the total length (in mm) of the one ormore pellets added to the canister, the total calculated surface area(in mm²) of the one or more pellets added to the canister, and the finalwater content in the HFA-134-a propellant (in ppm) are reported.

TABLE 1 Total surface Water Content Total length area of of HFA-134aNumber of of pellet(s) pellet(s) after 1 Finished pellets added to addedto Month of Canister added to Canister Canister Storage DesignationCanister (mm) (mm²) (ppm) Comparative A 0 0 0 102 Comparative B 0 0 0 881 1 2.12 72.6 185 2 1 2.25 74.6 183 3 1 4.13 104.1 220 4 1 6.02 133.8260 5 1 7.94 164.0 299 6 2 10.29 240.2 358 7 2 18.45 368.4 442 8 3 30.05589.8 523 9 8 80.57 1579.7 635

Example 2

Finished metered dose inhaler canisters were prepared, stored, andanalyzed for water content following the method described in Example 1with the exception that HFA-227 propellant was added to the cans,instead of HFA-134a propellant.

Nine different canisters (canisters 10-18) were prepared according tothis procedure, each with a different number of pellets and/or pelletlength. Two additional canisters were prepared as comparative examples(C and D) in which the same procedure was followed except that nopellets were added to the canister. The comparative canisters provided abaseline water content for HFA-227 filled canisters. The finishedcanisters were stored in a valve-up orientation at ambient conditionsfor one month. At the end of the storage period, the water content inthe propellant of each canister was determined using a Karl Fischertest. In Table 2, for each canister the total length (in mm) of the oneor more pellets added to the canister, the total calculated surface area(in mm²) of the one or more pellets added to the canister, and the finalwater content (in ppm) in the HFA-227 propellant are reported.

TABLE 2 Total surface Water Content Total length area of of HFA-227Number of of pellet(s) pellet(s) after 1 Finished pellets added to addedto Month of Canister added to Canister Canister Storage DesignationCanister (mm) (mm²) (ppm) Comparative C 0 0 0 75 Comparative D 0 0 0 7510 1 2.10 72.3 169 11 1 2.25 74.6 159 12 1 4.13 104.1 179 13 1 6.02133.8 200 14 1 7.94 164.0 219 15 2 10.26 239.7 254 16 2 18.07 362.4 29617 3 30.21 592.3 323 18 8 80.49 1578.5 355

Example 3

Albuterol sulfate and ipratropium bromide monohydrate were eachmicronized to provide a mass median diameter (MMD) range of about 1-5microns. Pellets of differing lengths were cut from the nylon 6,6 rodsusing a scalpel, and were then soaked in a water bath at roomtemperature for 24 hours. The pellets were removed from the water bathand their surfaces were thoroughly wiped dry using paper toweling. Oneor more pellets were then added to an aluminum can and the can was thenimmediately cold-filled with the drug suspension formulation of Table 3(albuterol sulfate and ipratropium bromide monohydrate in propellant).The propellant was a pre-mixed solution (50:50 by weight) of HFA-134aand HFA-227. The bulk formulation for cold filling individual canisterswas prepared by combining the micronized albuterol sulfate andipratropium bromide monohydrate with a portion of the propellantsolution (about half of the total propellant) in a vessel chilled to atemperature below −50° C. The resultant suspension was high shear mixedfor 5-10 minutes using a Silverson mixer (Silverson, East Longmeadow,Mass.). The remaining propellant was then added to the chilled vessel,and high shear mixing was continued for an additional 10 minutes.

Each canister was completed by being cold filled with a total ofapproximately 13-14.5 grams of the formulation, followed by crimping ofthe metering valve to the can to form a finished metered dose inhalercanister.

Seven different canisters (canisters 19-25) were prepared according tothis procedure, with each canister having a single pellet of varyinglength (pellet lengths ranging from 1.65-18.02 mm). Two additionalcanisters were prepared as comparative examples (E and F) in which thesame procedure was followed except that no pellet was added to thecanister. The comparative canisters provided a baseline water contentfor the canisters filled with the formulation. The finished canisterswere stored in a valve-up orientation at ambient conditions for onemonth. At the end of the storage period, the water content in theformulation of each canister was determined using a Karl Fischer test.In Table 4, for each canister the total length (in mm) of the pelletadded to the canister, the total calculated surface area (in mm²) of thepellet added to the canister and the final water content of theformulation (in ppm) are reported.

TABLE 3 Suspension Formulation of Example 3 Amount FormulationIngredient (in Percent by Weight) Albuterol sulfate 0.295 IpratropiumBromide Monohydrate 0.052 HFA-134a/HFA-227 (50:50 by weight) 99.653

TABLE 4 Total surface Water Content Total length area of of the Numberof of pellet(s) pellet(s) Formulation Finished pellets added to added toafter 1 Month Canister added to Canister Canister of Storage DesignationCanister (mm) (mm²) (ppm) Comparative E 0 0.00 0.0 62 Comparative F 00.00 0.0 62 19 1 1.65 65.2 117 20 1 2.62 80.4 138 21 1 4.04 102.7 141 221 6.22 137.0 165 23 1 10.19 199.3 195 24 1 14.05 260.0 230 25 1 18.02322.3 249

Example 4

Finished metered dose inhaler canisters were prepared, stored, andanalyzed for water content following the method described in Example 3with two exceptions. First, the nylon pellets were soaked in water for12 hours, instead of 24 hours. Second, the total length of the nylonpellets added to a canister was greater than for any of the canisters ofExample 3.

Two different canisters (canisters 26-27) were prepared according tothis procedure, each with a different number of pellets and/or pelletlength. Two additional canisters were prepared as comparative examples(G and H) in which the same procedure was followed except that nopellets were added to the canister. The comparative canisters provided abaseline water content for canisters filled with the formulation. Thefinished canisters were stored in a valve-up orientation at ambientconditions for one month. At the end of the storage period, the watercontent in the formulation of each canister was determined using a KarlFischer test. In Table 5, for each canister the total length (in mm) ofthe one or more pellets added to the canister, the total calculatedsurface area (in mm²) of the one or more pellets added to the canisterand the final water content of the formulation (in ppm) are reported.

TABLE 5 Total surface Water Content Total length area of of the Numberof of pellet(s) pellet(s) Formulation Finished pellets added to added toafter 1 Month Canister added to Canister Canister of Storage DesignationCanister (mm) (mm²) (ppm) Comparative G 0 0 0 113 Comparative H 0 0 0117 26 3 30.55 597.7 422 27 8 80.40 1577.1 468

Example 5

Finished metered dose inhaler canisters were prepared, stored, andanalyzed for water content following the method described in Example 3with the exception that the nylon pellets were soaked in water for aminimum of 60 hours, instead of 24 hours.

Five different canisters (canisters 28-32) were prepared according tothis procedure each with each canister having a single pellet of varyinglength (pellet lengths ranging from 2.41-10.17 mm). Two additionalcanisters were prepared as comparative examples (I and J), in which thesame procedure was followed except that no pellets were added to thecanister. The comparative canisters provided a baseline water contentfor canisters filled with the formulation. The finished canisters werestored in a valve-up orientation at ambient conditions for one month. Atthe end of the storage period, the water content in the formulation ofeach canister was determined using a Karl Fischer test. In Table 6, foreach canister the total length (in mm) of the added to the canister, thetotal calculated surface area (in mm²) of the pellet added to a canisterand the final water content of the formulation (in ppm) are reported.

TABLE 6 Total surface Water Content Total length area of of the Numberof of pellet(s) pellet(s) Formulation Finished pellets added to added toafter 1 Month Canister added to Canister Canister of Storage DesignationCanister (mm) (mm²) (ppm) Comparative I 0 0 0 113 Comparative J 0 0 0117 28 1 2.41 77.1 224 29 1 4.28 106.5 269 30 1 6.30 138.2 318 31 1 8.13167.0 361 32 1 10.17 199.0 370

1. A method of maintaining a water level in a pressurized aerosolcanister comprising a composition, the composition comprising a liquidcomprising a propellant, the propellant comprising one or more ofHFA-134a and HFA-227; one or more pharmaceutical active agents dissolvedor dispersed in the liquid; and one or more nylon pellets; and water,wherein at least some of the water is adsorbed on or absorbed within theone or more nylon pellets, the method comprising soaking the one or morenylon pellets in water to form one or more water soaked pellets,optionally removing water from the surface of the one or more watersoaked pellets, and forming the aerosol composition.
 2. The method ofclaim 1, wherein at least one of the one or more pharmaceutical activeagents is a hydrate.
 3. The method of claim 1, wherein at least one ofthe one or more pharmaceutical active agents is a hydrate of ipratropiumor a hydrate of an ipratropium salt.
 4. The method of claim 1, whereinat least one of the one or more pharmaceutical active agents isipratropium bromide monohydrate.
 5. The method of claim 1, wherein thecomposition further comprises albuterol.
 6. The method of claim 1,wherein the nylon is nylon 6,6.
 7. The method of claim 1, wherein thepropellant comprises HFA-134a.
 8. The method of claim 1, wherein atleast some of the water is dissolved or dispersed in the liquid and theconcentration of the water dissolved or dispersed in the liquid isbetween 50 ppm and 500 ppm based on the liquid and any componentsdissolved or dispersed in the liquid. 9-15. (canceled)